[08-20-2010] The U.S. Food and Drug Administration (FDA) is
evaluating clinical trial data that suggest patients taking Stalevo
(a combination of carbidopa/levodopa and entacapone) may be at an
increased risk for cardiovascular events (heart attack, stroke, and
cardiovascular death) compared to those taking carbidopa/levodopa
(sold as the combination product, Sinemet).

Both Stalevo and Sinemet have been shown to be effective
treatments for the symptoms of Parkinson's disease. The addition of
entacapone to carbidopa/levodopa has been shown to lead to a
greater degree of improvement in some of the symptoms of
Parkinson's disease than treatment with carbidopa/levodopa
alone.

Entacapone is also available as a single-ingredient product
(sold under the brand name Comtan) to be always administered in
association with carbidopa/levodopa (entacapone has no
antiparkinsonian effect of its own).

It is estimated that 154,000 patients were dispensed a
prescription for Stalevo from its approval in June 2003 through
October 2009.

At this time, FDA's review of the potential cardiovascular
risk with Stalevo is ongoing.

Healthcare professionals should regularly evaluate the
cardiovascular status of patients who are taking Stalevo,
especially if they have a history of cardiovascular
disease.

Patients should not stop taking Stalevo unless told to do so
by their healthcare professional.

FDA is exploring additional ways to assess whether Stalevo
increases the risk of cardiovascular events, and will update the
public when this review is complete.

The data being evaluated are from a meta-analysis that combined
the cardiovascular-related findings from 15 clinical trials
comparing Stalevo to carbidopa/levodopa; that is, examining the
effect of adding entacapone to carbidopa/levodopa. In the
meta-analysis, a small increased risk of cardiovascular events in
the Stalevo group was found. However, several factors make
evaluation of these findings difficult. First, the clinical trials
in the meta-analysis were not specifically designed to evaluate
cardiovascular safety. In addition, the majority of patients had
preexisting risk factors for cardiovascular disease, so that even
small differences in the level of these risks could affect the
outcome markedly. Moreover, many of the events occurred in a single
trial. It should also be noted that cardiovascular events are not
uncommon in people with Parkinson's disease in the age range
studied in these trials.

Additional Information for
Patients

FDA has not concluded that Stalevo increases your risk of heart
attack, strokes, or cardiovascular death. The Agency is still
reviewing the available information about this safety concern.

Do not stop taking your Stalevo or Comtan unless told to do so
by your healthcare professional.

Make sure your healthcare professional knows if you have a
history of cardiovascular disease.

Talk to your healthcare professional if you have concerns about
Stalevo or Comtan.

Additional Information for
Healthcare Professionals

In a meta-analysis that included 15 clinical trials comparing
entacapone/carbidopa/levodopa to carbidopa/levodopa alone, a small
increase in the risk of heart attack, stroke, or cardiovascular
death was found in the group treated with
entacapone/carbidopa/levodopa.

FDA is still reviewing the available information and has not
concluded that Stalevo increases a patient's risk for
cardiovascular events.

Follow the recommendations in the drug label when prescribing
Stalevo or Comtan.

Regular evaluation of the cardiovascular status of patients who
are taking Stalevo is recommended.

Data Summary

FDA's decision to conduct a meta-analysis was based on findings
from the Stalevo Reduction
In Dyskinesia
Evaluation – Parkinson's
Disease or STRIDE-PD trial, which reported an
imbalance in the number of myocardial infarctions in patients
treated with Stalevo compared to those receiving only
carbidopa/levodopa. Although myocardial infarction, cardiac
irregularities, hypertension, and palpitations have been reported
with levodopa, previous clinical trials with Stalevo did not show
an imbalance in myocardial infarction, stroke, and cardiovascular
death. The majority of these trials, however, were of 6 months
duration or less and had relatively few events.

In STRIDE-PD, 373 patients received Stalevo and 372 received
carbidopa/levodopa. Treatment lasted between 2.6 years and 4 years
(mean duration: 2.7 years). The average age of patients in the
trial was approximately 60 years. Seven myocardial infarctions and
one cardiovascular death were reported in the Stalevo group and no
myocardial infarctions or cardiovascular deaths were reported in
the carbidopa/levodopa group.

Based on the findings from the STRIDE-PD trial, FDA conducted a
meta-analysis that combined the cardiovascular findings from 15
clinical trials in approximately 4,800 patients comparing
entacapone/carbidopa/levodopa to carbidopa/levodopa without
entacapone. A composite endpoint of myocardial infarction, stroke,
and cardiovascular death was used to represent cardiovascular
events. Twenty-seven cardiovascular events were reported in the
entacapone/carbidopa/levodopa group compared to 10 in the
carbidopa/levodopa group. This resulted in a relative risk of 2.46
(95% Confidence Interval: 1.19, 5.09). When the STRIDE-PD trial was
removed from the analysis, the relative risk was 1.67 (95%
Confidence Interval: 0.77, 3.61), i.e., a finding that was no
longer statistically significant.

Although there was a statistically significant increased risk of
cardiovascular events in the entacapone/carbidopa/levodopa group
compared to carbidopa/levodopa group when STRIDE-PD is included,
the following factors make it difficult to draw sound conclusions
based on this finding:

Trials included in the meta-analysis were not specifically
designed to evaluate Stalevo's cardiovascular safety.

Most patients had preexisting risk factors for cardiovascular
disease.

Eleven of the trials had a duration of fewer than six months,
possibly not long enough to evaluate cardiovascular risk (7 of the
8 events in the STRIDE-PD trial occurred after 6 months of Stalevo
treatment).

The safety signal is largely driven by one trial, STRIDE-PD,
with a relative risk of 2.46 (95% Confidence Interval: 1.19, 5.09)
when STRIDE-PD is included and a relative risk of 1.67 (95%
Confidence Interval: 0.77, 3.61) when STRIDE-PD is not
included.

Adverse event narratives were poor and cardiovascular event
validation was difficult in many cases.

An assumption of the meta-analysis was that covariates were
balanced through randomization in the 15 trials.

No data was available on treatment discontinuation or trial
discontinuation. It is assumed that any discontinuation was
independent from the risk of adverse events in both treatment
groups.

There was no access to detailed data at the level of individual
patients to allow for an exploration of the potential effect of
covariates on the finding and a better assessment of the causal
relationship between Stalevo and cardiovascular events.

FDA is exploring additional ways to assess whether Stalevo
increases the risk of cardiovascular events, and will update the
public when this review is complete.

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